Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease; Randomized Comparison of LDL-cholesterol Targeting <70 Versus <55mg/dL; Ez-PAVE Trial

NCT ID: NCT04626973

Last Updated: 2025-11-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 3048 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-15
• Study Completion Date: 2025-09-24

Brief Summary

Although the clinical efficacy of LDL-cholesterol lowering therapy has been proven with strong evidences and emphasized, there are also growing concerns that intensive lipid-lowering therapy would be related to increased risk of adverse effects. In addition, statin potency from recent guidelines was set from the studies composed of mainly Caucasian population, although there is an inconsistency of statin effect according to ethnicity. Asian population showed more profound LDL reduction not only from high potent statin but also from moderate to low potent statin. Conventional strategies for lowering LDL-cholesterol focused on statins, therefore doubling of previously described dose of statin would be common way in patients with inadequate LDL-cholesterol levels. Adding ezetimibe will be an alternative strategy not only to lower LDL-cholesterol level and also to reduce the need of dosage of high-intensity statin to achieve sufficient LDL-cholesterol lowering effect. However, studies regarding the effect of intensive-targeting of lipid-lowering therapy and therapy regimens are lacking. Thus, on these basis, we sought to evaluate whether intensive-targeting of lipid-lowering therapy will have more prominent beneficial effect compared to conventional-targeting in patients with documented ASCVD with either an ezetimibe/statin combination therapy or a statin monotherapy.

Detailed Description

All eligible patients who have documented ASCVD will be enrolled according to inclusion/exclusion criteria after voluntary agreement with informed consent. At the time of enrollment, we will stratify all patients according to LDL-cholesterol <100mg/dL, DM, and acute coronary syndrome, and randomly assign them in two groups according to LDL-cholesterol targeting level with a 1:1 ratio: "Intensive-targeting group" vs. "Conventional-targeting group". In addition, patients in each group will be randomly assigned to receive two lipid-lowering therapy regimen with a 1:1 ratio: "Ezetimibe/Statin combination therapy" vs. "Statin monotherapy". Patients allocated to each treatment group will receive lipid-lowering therapy with following protocols.

Conditions

Atherosclerotic Cardiovascular Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intensive-targeting group

Group Type: EXPERIMENTAL

Ezetimibe/Statin Combination therarpy (ezetimibe plus rosuvastatin)

Intervention Type: DRUG

For statin naive patients, patients would initially receive Ezetimibe 10mg plus Rosuvastatin 10 or 20 mg.

For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Statin monotherapy (rosuvastatin or atorvastatin)

Intervention Type: DRUG

For statin naive patients, patients would initially receive Rosuvastatin 20mg or Atorvastatin 40 or 80 mg.

For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Conventional-targeting group

Group Type: ACTIVE_COMPARATOR

Ezetimibe/Statin Combination therarpy (ezetimibe plus rosuvastatin)

Intervention Type: DRUG

For statin naive patients, patients would initially receive Ezetimibe 10mg plus Rosuvastatin 5 or 10mg.

For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Statin monotherapy (rosuvastatin or atorvastatin)

Intervention Type: DRUG

For statin naive patients, patients would initially receive Rosuvastatin 10 or 20mg or Atorvastatin 20 or 40mg. For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (\<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Interventions

Ezetimibe/Statin Combination therarpy (ezetimibe plus rosuvastatin)

For statin naive patients, patients would initially receive Ezetimibe 10mg plus Rosuvastatin 10 or 20 mg.

For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Intervention Type: DRUG

Statin monotherapy (rosuvastatin or atorvastatin)

For statin naive patients, patients would initially receive Rosuvastatin 20mg or Atorvastatin 40 or 80 mg.

For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Intervention Type: DRUG

Ezetimibe/Statin Combination therarpy (ezetimibe plus rosuvastatin)

For statin naive patients, patients would initially receive Ezetimibe 10mg plus Rosuvastatin 5 or 10mg.

For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Intervention Type: DRUG

Statin monotherapy (rosuvastatin or atorvastatin)

For statin naive patients, patients would initially receive Rosuvastatin 10 or 20mg or Atorvastatin 20 or 40mg. For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (\<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age 19-80 years

2. Documented atherosclerotic cardiovascular disease (ASCVD)

• Previous acute coronary syndrome (myocardial infarction [MI] or unstable angina),
• Or stable angina with imaging or functional studies
• Or coronary revascularization (percutaneous coronary intervention [PCI], coronary artery bypass graft [CABG], and other arterial revascularization procedures)
• Or stroke and transient ischemic attack (TIA)
• Or peripheral artery disease

Exclusion Criteria

1. LDL-cholesterol level less than 70 mg/dL without statin therapyAllergy or hypersensitive to ezetimibe or statin

2. Active liver disease or persistent unexplained serum AST/ALT elevation more than 2 times the upper limit of normal range

3. Allergy or hypersensitivity to any statin or ezetimibe

4. Solid organ transplantation recipient

5. Pregnant women, women with potential childbearing, or lactating women

6. Life expectancy less than 3 years

7. Inability to follow the patient over the period of 1 year after enrollment, as assessed by the investigator

8. Inability to understand or read the informed content

• Minimum Eligible Age: 19 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Yonsei University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Byeong-Keuk Kim, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Severance Hospital

Locations

Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine

Seoul, , South Korea

Countries

South Korea

Other Identifiers

4-2020-0903

Identifier Type: -

Identifier Source: org_study_id